1,2-Benzisoxazole-3-methanesulfonic acid obtained by the sulfonation reaction of 1,2-benzisoxazole-3-acetic acid with chlorosulfonic acid is an intermediate of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide). Zonisamide is useful as an anti-epileptic medicine.
JP-A-53-77057 and Yakugakuzasshi, 116, 533-547 (1996) disclose a process for the preparation of 1,2-benzisoxazole-3-methanesulfonic acid which is produced from a reaction of chlorosulfonic acid and 1,2-benzisoxazole-3-acetic acid in the presence of dioxane in ethylene chloride (1,2-dichloroethane) or dichloromethane.
U.S. Pat. No. 6,841,683, in experiment number TN 2414, and US2003/0144527A1, in experiment number 4, disclose an example in which 1,2-benzisoxazole-3-acetic acid and chlorosulfonic acid are reacted in toluene, and in the reaction mixture there are 63.5%, 3% and 32% of the sodium salt of 1,2-benzisoxazole-3-methanesulfonic acid, the disulfonated benzisoxazole derivative that is a by-product and a starting material (1,2-benzisoxazole-3-acetic acid) respectively. However, U.S. Pat. No. 6,841,683 and US2003/0144527A1 apparently do not disclose or describe the isolation yield and purity of 1,2-benzisoxazole-3-methanesulfonic acid.
U.S. Pat. No. 4,172,896, JP-A-53-77057, JP-A-54-163823 and J. Med. Chem., 22, 180 (1979) disclose a process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide which is produced by a method comprising a step of reacting sodium 1,2-benzisoxazole-3-methanesulfonate isolated as an solid form with phosphorus oxychloride (phosphoryl chloride), and followed by reacting with ammonia gas in ethyl acetate. Using dry ammonia gas is disclosed, for instance, in U.S. Pat. No. 4,172,896 and JP-A-53-77057.
U.S. Pat. No. 6,936,720 discloses a process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide which is produced by a method comprising a step of reacting sodium 1,2-benzisoxazole-3-methanesulfonate with SOCl2/DMF in toluene, and followed by reacting with ammonia gas.
U.S. Pat. No. 6,900,333 discloses a process for the preparation of 1,2-dichlorethane free crystals of 1,2-benzisoxazole-3-methanesulfonamide that is manufactured using 1,2-dichlorethane as a solvent.
While sulfonation of 1,2-benzisoxazole-acetic acid is known to proceed with chlorosulfonic acid and dioxane, it is desirable to avoid the use of dioxane.
Conducting the sulfonation of 1,2-benzisoxazole-3-acetic acid directly with chlorosulfonic acid serving as both a solvent and the sulfonating agent has been reported in Chem. Pharm. Bull., 26, 3498-3503 (1978). The reaction is, however, reported to be quite non-selective and substantial amounts of an undesired di-sulfonated by-product are reportedly produced.
The present inventors turned their attention to toluene as a solvent and concentrated on a method for producing 1,2-benzisoxazole-3-methanesulfonamide from 1,2-benzisoxazole-3-acetic acid as a starting material in a one-pot reaction that does not require isolating any intermediates. Advantages to using toluene as a solvent in such a manufacturing process include 1) reducing usage of a relatively toxic halogenated hydrocarbon, such as 1,2-dichloroethane, 2) ready removal of water from. toluene by azeotropic distillation, which water is from an aqueous sodium hydroxide solution that is used in the manufacturing process, and 3) stability (chemical inertness) to chemical agents such as sodium hydroxide, phosphorus oxychloride and ammonia.
However, it is known that an aromatic compound such as toluene reacts with chlorosulfonic acid easily to yield sulfonic acid derivatives, as seen for example, from S. Patai and Z. Rappoport, The chemistry of sulfonic acids, esters and their derivatives, pages 354-355, 1991, John Wiley & Sons. Consequently, when chlorosulfonic acid was actually added into a mixture of toluene and 1,2-benzisoxazole-3-acetic acid, and the mixture was allowed to react, it was found that sulfonation reaction products of toluene with chlorosulfonic acid and 1,2-benzisoxazole-3-methanesulfonic acid were formed. The aforesaid reaction mixture contained 44% of sulfonation by-product(s), 25% of the desired sulfonation reaction product, and 29% starting material (1,2-benzisoxazole-3-acetic acid) as reported in Reference Example 5 herein. Thus, a simple method such as heating the mixture of 1,2-benzisoxazole-3-acetic acid and toluene with an addition of chlorosulfonic acid is non-selective and can result in the simultaneous sulfonation of toluene, and it is not easy to produce 1,2-benzisoxazole-3-methanesulfonic acid effectively.
In addition, JP-A-53-77057 discloses that dioxane is used as a Lewis base in a sulfonation reaction of 1,2-benzisoxazole-3-acetic acid, but it does not disclose a Lewis base other than dioxane, and especially a Lewis base having low toxicity is apparently not disclosed.
There remains a need for a facile method(s) that is selective to the desired intermediate(s) that are useful in the synthesis of zonisamide, with a sufficiently high yield, and to a facile method for making zonisamide in high purity that avoids the use of dioxane and preferably does not require isolation of any solid intermediates.